Alzheimers disease (AD) represents one of the greatest health problems in industrialized countries considering the ageing population. Only four drugs are currently approved for the treatment of this disease. As these drugs are characterized with a limited time efficacy, it has become urgent to develop additional innovative AD treatments. Amongst the approaches that are actively investigated, the one consisting in potentiating a subclass of glutamate receptors appears attractive. This well advanced pharmacological approach includes three major classes of compounds amongst which appear the benzothiadiazine 1,1-dioxides. The present thesis is a pursuit of the preliminary efforts that were published in 1998 and 2001 by our team. Based on promising in vitro results obtained with the lead compound 59, pharmacomodulations around 59s structure have been achieved in order to enhance its in vivo activity and to optimize its pharmacokinetic parameters. First efforts were devoted to exploratory synthesis where attention was paid to the impact of the substituent introduced at the 7-position. Moreover, some pyridothiadiazine dioxides as well as thienothiadiazine dioxides were prepared. The most important part of our pharmacomodulations was focused on the thiadiazine ring system. Considering that the poor in vivo results obtained with 59 could be due to a metabolic weakness of the latter, the introduction of fluorine atoms was tempted as a lead optimization strategy. This approach was successful, since it led to the synthesis of 95b which was selected for further pharmacological evaluations. This new lead compound was shown to exert significant cognitive-enhancing effects in vivo after oral administration to Wistar rats. Moreover, the study of the metabolic degradation of 95b allowed the assessment of the starting hypothesis that had dictated the pharmacomodulations philosophy. Finally, additional exploratory pharmacomodulations were achieved notably leading to the preparation of a quinazolinone series and 1,4-benzothiazine compounds. This research allowed to significantly improve the pharmacokinetic profile of our series and led to the identification of 95b as a new lead compound. However, many pharmacomodulations remain to be explored. The data collected during this thesis are appealing further studies. Efforts in the near future should lead to the design of novel drug candidates among which a future innovative AD treatment could emerge. Au vu du vieillissement de la population dans les pays industrialisés, la maladie dAlzheimer constitue un problème majeur en termes de santé publique. A lheure actuelle, seuls quatre médicaments sont utilisés pour traiter cette maladie. Sachant que ces substances nont quune efficacité limitée, la conception de nouveaux médicaments actifs contre cette pathologie apparaît comme une priorité. Dans cette optique, la potentialisation des récepteurs glutamatergiques de sous-type AMPA semble une approche thérapeutique intéressante. Parmi les composés étudiés dans cette voie, apparaissent les benzothiadiazine dioxydes. Cette thèse sinscrit dans la continuité des recherches publiées en 1998 et 2001 par notre équipe et poursuit les pharmacomodulations entamées autour du composé leader 59. Ce travail sest principalement focalisé sur lamélioration de lactivité in vivo de ce dérivé et sur loptimisation de ses paramètres pharmacocinétiques afin dobtenir un candidat médicament potentiel. Notre attention sest tout dabord portée sur la subsitution aromatique en position 7. Par ailleurs, plusieurs séries pyrido- et thiénothiadiazines ont été également préparées. Ensuite, en postulant que le manque dactivité in vivo du composé 59 pouvait être dû à une faiblesse métabolique de ce composé, lintroduction judicieuse datomes de fluor a été choisie comme stratégie doptimisation. Cette approche nous a notamment amené à lidentification du composé 95b. Ce dérivé sest montré particulièrement actif dans un test de reconnaissance dobjets chez le rat Wistar. Ce résultat encourageant a amené à réaliser toute une série dévaluations pharmacologiques sur ce produit, afin de caractériser son mécanisme daction. Les données récoltées à lissue de ces investigations suggèrent que le composé 95b présente un intérêt potentiel en tant quagent procognitif. Dautre part, létude du profil de dégradation métabolique de ce dérivé a permis de confirmer lhypothèse qui avait dicté lintroduction datomes de fluor. Enfin, des pharmacomodulations supplémentaires ont été réalisées de façon exploratoire et ont entre autres débouché sur une série de quinazolinones et une série de 1,4-benzothiazines. Les travaux réalisés au cours de cette thèse ont permis daméliorer grandement le profil pharmacocinétique des séries explorées. Néanmoins, de nombreuses pharmacomodulations restent à explorer. Des études complémentaires savèrent nécessaires et devraient déboucher sur de nouveaux candidats médicaments innovants, parmi lesquels pourraient figurer un futur traitement de la maladie dAlzheimer.

Spatial navigation in humans correlates with activity of cells in hippocampus that respond when we traverse specific locations in our environment. Hippocampal pyramidal cells in rodents called "place cells" may contribute to episodic memory by encoding location in physical space. Place cells display plasticity by "remapping" or altering their firing rates and patterns of activity in response to changes in spatial environment. Impaired remapping may underlie age-related deficits in spatial memory tasks. Using in vivo high-density electrophysiology to record place cell activity in awake, behaving rats, we tested the hypothesis that CA3 neuron hyperactivity in aged animals could be normalized by pharmacotherapy. Results show that acute, systemic administration of low dose levetiracetam and sodium valproate ameliorates deficits in the aged hippocampal network by reducing firing rates, decreasing place field area, and increasing the spatial selectivity of CA3 place cells. We then tested the hypothesis that place cell activity, field area, and spatial selectivity may be an indicator for therapeutic enhancement of spatial memory in young adult rats. The results demonstrate that α5IA enhances hippocampal-dependent spatial memory as measured by the location novelty recognition task in rats, consistent with the previously established action of α5IA as an enhancer of spatial memory in the water maze test. Electrophysiological recordings on the same animals carried out in parallel demonstrate that α5IA increases place cell firing rates, reduces field area, and increases spatial selectivity. Together, these results suggest that reducing place field area and enhancing spatial selectivity correlate with the age-independent therapeutic improvement of spatial memory. The increase in place cell firing rates by α5IA likely results from its known action as a negative allosteric modulator of α5-subunit-containing receptors (α), which are located extrasynaptically at the base of dendritic spines on CA1 and CA3 pyramidal cells. Thus, to potentially target extrasynaptic tonic inhibition in the hippocampus, we synthesized and validated two α specific miRNAs as a platform for future attempts to improve spatial memory in young adult and aging animals via molecular genetics.